Pyrimidines and variants thereof, and uses therefor
The present disclosure provides pyrimidine compounds of Formula 1 and uses thereof for example, for the potential treatment of diseases associated with P2X purinergic receptors. In certain aspects, the present disclosure provides P2X3 and/or P2X2/3 antagonists which are useful, for example, for the potential treatment of visceral organ, cardiovascular and pain-related diseases, conditions and disorders.
1. A compound of Formula 1:
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from O and S;
X 1 is N;
X 2 is CR 3 ;
X 3 is CR 4 ;
X 4 is CR 5 ;
X 5 is N or CR 6 ;
Y is —NR d R e , wherein one of R d and R e is hydrogen, and the other is hydrogen
D is absent;
R 1 is selected from C 1-12 -alkyl; C 2-12 -alkenyl; C 2-12 -alkynyl; C 3-12 -cycloalkyl; C 3-12 -cycloalkenyl; halo; C 1-12 -haloalkyl; and C 1-12 -hydroxyalkyl;
R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen; C 1-12 -alkyl; C 2-12 -alkenyl; C 2-12 -alkynyl; amino; halo; amido; C 1-12 -haloalkyl; C 1-12 -alkoxy; hydroxy; C 1-12 -haloalkoxy; nitro; C 1-12 -hydroxyalkyl; C 2-12 -alkoxyalkyl; C 1-12 -hydroxyalkoxy; C 3-12 -alkynylalkoxy; C 1-12 -alkylsulfonyl; C 5-12 -arylsulfonyl; cyano; C 6-12 -aryl; C 5-12 -heteroaryl; C 3-12 -heterocyclyl; C 4-12 -heterocyclylalkoxy; C 6-12 -aryloxy; C 5-12 -heteroaryloxy; C 7-12 -arylalkyloxy; C 6-12 -heteroaralkyloxy; optionally substituted phenoxy; —(CH 2 ) m —(Z) n —(CO)—R f and —(CH 2 ) m —(Z) n —SO 2 —(NR g ) n′ —R f , where m, n and n′ are each independently 0 or 1;
Z is O or NR g ;
R f is selected from hydrogen, C 1-12 -alkyl, hydroxy, C 1-12 -alkoxy, amino, C 1-12 -hydroxyalkyl and C 2-12 -alkoxyalkyl;
each R g is independently hydrogen or C 1-12 -alkyl;
R 6 is selected from hydrogen and C 1-12 -alkyl; and
R 7 is hydrogen.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 5 is N, providing compounds of Formula 1l, as follows:
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 5 is CR 6 , providing compounds of Formula 1m, as follows.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is O.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is S.
6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from:
7. A composition which comprises an inert carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
8. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein X 5 is CH.